Substituted phenoxyalkanolamines and phenoxyalkanol-cycloalkylamines, and intermediate products

ABSTRACT

New substituted phenoxyalkanolamines and phenoxyalkanol-cycloalkylamines of the general formula I ##STR1## in which R 1  and R 2 , which can be identical or different, denote alkyl groups with in each case 1 to 4 carbon atoms, or R 1  and R 2  together denote the group --(CH 2 ) n  --, wherein n is the number 4 or 5, R 3  denotes hydrogen, or an alkyl group or an acyl group with in each case 1 to 6 carbon atoms, R 4  denotes an alkyl group with 1 to 4 carbon atoms or the cyclopropylmethyl group and R 5  denotes hydrogen halogen or alkyl, and acid addition salts thereof, have a cardioselective β 1  -adrenolytic and hypotensive action. They can be used as medicaments for the treatment of angina pectoris, hypertension and arrhythmias.

This is a continuation of application Ser. No. 722,906 filed 4/12/85,now abandoned, which is a continuation of Ser. No. 450,161 filed12/16/82, now abandoned.

The invention relates to new substituted phenoxyalkanolamines andphenoxyalkanol-cycloalkylamines of the general formula I ##STR2## inwhich R¹ and R², which can be identical or different, denote alkylgroups with in each case 1 to 4 carbon atoms, or R¹ and R² togetherdenote the group --(CH₂)_(n) --, wherein n is the number 4 or 5, R³denotes hydrogen, or an alkyl group or an acyl group with in each case 1to 6 carbon atoms, R⁴ denotes an alkyl group with 1 to 4 carbon atoms orthe cyclopropylmethyl group and R⁵ denotes hydrogen, halogen or alkyl,and acid addition salts thereof, processes for their preparation andtheir use in pharmacetical products.

The invention furthermore relates to new substitutedphenoxynitroalkanols and phenoxyhydroxyalkylnitrocycloalkanes of thegeneral formula II ##STR3## in which R¹ and R², which can be identicalor different, denote alkyl groups with in each case 1 to 4 carbon atoms,or R¹ and R² together denote the group --(CH₂)_(n) --, wherein n is thenumber 4 or 5, R⁴ denotes an alkyl group with 1 to 4 carbon atoms or thecyclopropylmethyl group and R₅ denotes hydrogen, halogen or alkyl,processes for their preparation and their use as intermediate productsfor the preparation of the compounds of the general formula I accordingto the invention.

The intermediate products of the formula II also have therapeuticproperties. In particular, they can be used like the end products of thegeneral formula I according to the invention.

The new compounds of the general formulae I and II contain one or twoasymmetric carbon atoms. The invention thus also relates to variousoptical isomers and the diastereo isomers, as well as the addition saltsof these compounds with acids. Racemates can be resolved into theiroptical antipodes by methods which are known per se, for example byusing optically active acids, such as tartaric acid, camphorsulphonicacid or dibenzoyltartaric acid, or as esters or ethers with opticallyactive components or via compounds which include urea.

The invention furthermore relates to new substitutedphenoxyacetaldehydes of the general formula III ##STR4## in which R⁴denotes an alkyl group with 1 to 4 carbon atoms or the cyclopropylmethylgroup and R⁵ denotes hydrogen, halogen or alkyl, processes for theirpreparation and their use as intermediate products for the preparationof the compounds of the general formulae I and II according to theinvention.

Compounds which block beta-receptors but do not have the substituents,according to the invention, of the α-carbon atom in the propoxy sidechain are already known from German Offenlegungsschriften Nos. 2,106,209and 2,649,605.

The definition chosen here for the alkyl radicals R¹, R², R³, R⁴ and R⁵and the alkyl radicals of the acyl group R³ means both straight-chainand branched aliphatic hydrocarbon radicals containing 1 to 6 carbonatoms, such as, for example, the methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, sec.-butyl group, isobutyl group,tert.-butyl group, n-pentyl group, isopentyl group, neopentyl group,amyl group, n-hexyl group and isohexyl groups and the branched hexylgroups with a quaternary carbon atom. The methyl group, the ethyl groupand the propyl groups are particularly preferred.

R⁴ is preferably methyl, ethyl, isopropyl or cyclopropylmethyl.

Preferred acyl groups are alkanoyl groups with 1 to 6 carbon atoms, inparticular the formyl group, the acetyl group and the propionyl groups.

The radical R⁵ is preferably in the 2-position of the phenyl group or inthe ortho-position relative to the 2-hydroxy-3-amino-alkoxy side chain.The halogen radical R⁵ is fluorine, chlorine, bromine or iodine, but inparticular chlorine or bromine. The preferred alkyl radical R⁵ aremethyl and ethyl. R⁵ can also preferably be hydrogen.

Preferred compounds of the formulae I and II according to the inventionare those which, with the definition that R¹ and R² together denote thealkylidene groups --(CH₂)_(n) --, wherein n is 4 or 5, contain acyclopentane ring or cyclohexane ring. With this definition, they areeach formed including the α-carbon atom of the propoxy side chain.

Moreover, compounds of the formulae I and II in which R¹ and R² denotealkyl, in particular methyl, and also compounds in which R¹ and R² arealkyl groups, in particular methyl groups, and R⁴ is methyl orcyclopropylmethyl are preferred.

The new compounds of the general formula I according to the inventionand their acid addition salts have valuable therapeutic properties. Theyare distinguished by a cardioselective R₁ -adrenolytic action andhypotensive properties and are particularly suitable for the treatmentof angina pectoris, hypertension and cardiac arrhythmias. They arefurthermore suitable for the treatment of glaucoma, since they reducethe intraocular pressure.

The surprisingly high cardioselectivity of the new compounds depends,inter alia, on the di-substitution of the α-carbon atom of the propoxychain. Compounds in which R³ denotes a hydrogen atom have been found tobe particularly valuable in this connection. R¹ and R² are thenpreferably alkyl groups, in particular methyl groups.

The following compounds of the general formula I and salts thereof witha high therapeutic effect are particularly preferred, and in particularin the form of the racemates and in the form of optically activeisomers: 1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol and1-[4-(2-cyclopropylmethoxyethyl)-phenoxyl]-3-amino-3-methyl-butan-2-ol.

The compounds of the present invention can be used orally orparenterally in humans in a dosage of 20 mg to 1 g, preferably 50 mg to500 mg, per day in particular in divided doses, for example two or threetimes daily. In cats an intravenous dose of 1 to 10 mg/kg lowerstachycardia caused by isoprenaline by 25% (ED₂₅). For1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol, this dose is1.75 mg.

The daily dose is to be matched to the individual, because it depends onthe receptor sensitivity and the sympathicotonia of the patient.Advantageously, the treatment is started with low doses and thenincreased.

For the treatment of hypertension, daily doses of 50 to 200 mg, dividedinto two or three administrations, are preferred. Angina pectoris ispreferably treated with 50 to 200 mg per day, divided into twoadminstrations. For combating disorders in cardiac rhythm, 200 to 400 mgare administered daily, divided into two or three administrations.

For the treatment of increased intra-ocular pressure, 0.1 to 4% strengthaqueous isotonic solutions are applied locally to the eye in dosages ofone or more drops once or several times daily.

Pharmaceutical formulations which contain a compound of the formula I orpharmaceutically acceptable salts thereof, together with apharmaceutically acceptable diluent or excipient, are provided accordingto the invention.

The compounds according to the invention can be mixed with the customarypharmaceutically acceptable diluents or excipients and, if appropriate,with other auxiliaries, and can be administered, for example, orally orparenterally. They can be administered orally in the form of tablets,dragees, syrups, suspensions and liquids, or parenterally in the form ofsolutions or suspensions. Products to be administered orally can containone or more additives, such as sweeteners, aromatising agents, colorantsand preservatives. Tablets can contain the active compound mixed withthe customary, pharmaceutically acceptable auxiliaries, for exampleinert diluents, such as calcium carbonate, sodium carbonate, lactose andtalc, granulating agents and agents which promote disintegration of thetablets on oral administration, such as starch or alginic acid, binders,such as starch or gelatin, and lubricants, such as magnesium stearate,stearic acid and talc.

Examples of suitable excipients are milk sugar (lactose), gelatin, maizestarch, stearic acid, ethanol, propylene glycol, ethers oftetrahydrofuryl alcohol and water.

The tablets can be coated by known procedures, in order to delaydisintegration and resorption in the gastrointestinal tract, which meansthe activity of the active compound can extend over a longer period oftime. The active compound in the suspensions can also be mixed withauxiliaries which are customary for the preparation of suchcompositions, for example suspending agents, such as methylcellulose,tragacanth or sodium alginate, wetting agents, such as lecithin,polyethylene stearate and polyoxyethylene sorbitan monooleate, andpreservatives, such as ethyl para-hydroxybenzoate. Capsules can containthe active compound as the only constituent or as a mixture with a soliddiluent, such as calcium carbonate, calcium phosphate or kaolin. Theinjectable products are likewise formulated in a manner which is knownper se. The pharmaceutical products can contain the active compound inan amount of 0.1 to 90%, in particular 1 to 90%, the remainder being anexcipient or additive. In view of the preparation and administration,solid products, such as tablets and capsules, are preferred. Theproducts preferably contain the active compound in an amount of 50-100mg.

The compounds of the general formula I can be obtained by the followingprocesses:

The process for the preparation of the phenoxyalkanolamines andphenoxyalkanol-cycloalkylamines according to the general formula I, withthe abovementioned meaning of the radical R¹ to R⁵, is characterised inthat compounds of the general formula II ##STR5## with theabovementioned meaning of R¹, R², R⁴ and R⁵, are reduced and, ifappropriate, the amino group formed is alkylated or acylated.

The reduction is carried out either with palladium/hydrogen is alcoholicsolution in the presence of glacial acetic acid at 20° to 100° C. andunder 5 to 10 bar, or with zinc/hydrochloric acid at temperaturesbetween 50° to 70° C.

The amino group is alkylated either with an alkylating agent, such as,for example, dialkyl sulphate or tosyl alkyl esters, or by reaction withan aldehyde and subsequent reduction of the azomethine with aborohydride.

The methyl group (R³ =CH₃) is most advantageously introduced byformylation of the amino group with formic acid/acetic anhydride andsubsequent reduction of the formamide with lithium aluminium hydride.

The acyl groups are introduced with corresponding carboxylic acidanhydrides or carboxylic acid chlorides in the presence of a basiccatalyst, or by heating the components. The acyl esters which may beformed are split by alkaline hydrolysis.

The process for the preparation of the phenoxynitroalkanols andphenoxyhydroxyalkyl-nitrocycloalkanes according to the general formulaII, with the abovementioned meaning of the radicals R¹, R², R⁴ and R⁵,is characterised in that compounds of the general formula III ##STR6##with the abovementioned meaning of R⁴ and R⁵, are reacted with compoundsof the general formula IV ##STR7## with the abovementioned meaning of R¹and R².

The nitroalkanes, or nitrocyclopentane and nitrocyclohexane of theformula IV are condensed with the aldehyde of the formula III inalcoholic solution in the presence of sodium alcoholate at roomtemperature.

The nitro compounds of the formula IV are known, or they can be obtainedby known processes.

The process for the preparation of the aldehydes of the general formulaIII, with the abovementioned meaning of R⁴ and R⁵, is characterised inthat compounds of the general formula V ##STR8## with the meaning givenfor R⁴ and R⁵, are split by oxidation.

The compounds of the formula III are accessible, in particular, fromcompounds of the general formula V by oxidative splitting with lead-IVacetate in ethyl acetate, benzene or toluene or with sodiummeta-periodate in alcohol/water mixtures. The compounds of the formula Vused as starting materials are new compounds. They can be prepared fromthe corresponding known phenols by reaction with 2,3-epoxypropanol withcatalytic amounts of a quaternary amine in a solvent or by direct fusionof the reactants at temperatures between 120° to 160° C. They arevaluable intermediate products in the preparation of the end productsaccording to the invention. The invention also relates to these newstarting materials, the processes for their preparation and their use.

The compounds of the general formula I can be isolated from the reactionmixtures either as bases or in the form of their salts.

As bases, they can be converted into salts with suitable inorganic ororganic acids by known processes. Physiologically acceptable salts arepreferred. Examples of suitable inorganic acids are hydrogen halideacids, for example hydrochloric acid, or sulphuric acid, and examples ofsuitable organic acids are fumaric acid and maleic acid. For thepreparation, an alcoholic solution of a suitable acid is added to a hotalkaline solution of the base and, after ether has been added, the saltis obtained.

The examples which follow serve to illustrate the invention:

EXAMPLE 1

1-[4-(2-Methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol

19 g of 1-[4-(2-methoxyethyl)-phenoxy]-3-nitro-3-methyl-butan-2-ol arehydrogenated at 60° C. and under a pressure of 6 bar in a mixture of 250ml of ethanol and 50 ml of glacial acetic acid in the presence of 4 g ofpalladium-on-charcoal (10% Pd). After the mixture has been filtered andthe solvent has been evaporated off, the residue is rendered alkalinewith 2N NaOH and the mixture is extracted with CH₂ Cl₂. The organicphase is washed with water and dried with Na₂ SO₄ to give, afterevaporation, 15 g of the amine, which is converted into thehydrochloride with ethanol hydrochloric acid. Melting point: 120°-122°C. (ethyl acetate).

The compounds of the general formula I listed in Table 1 are preparedanalogously to Example 1 (in these Examples 2 to 5a, R⁵ is hydrogen):

                  TABLE 1                                                         ______________________________________                                        (R.sup.5 = H)                                                                 Ex-                                                                           am-                                                                           ple                                                                           No.  R.sup.1                                                                              R.sup.2  R.sup.3                                                                           R.sup.4   m.p. °C.                                                                      salt                                ______________________________________                                        2    CH.sub.3                                                                             CH.sub.3 H                                                                                  ##STR9## 176-177                                                                              fumarate                            3    CH.sub.3                                                                             CH.sub.3 H   CH.sub.2 CH.sub.2 CH.sub.3                                                              174-176                                                                              fumarate                            3a   CH.sub.3                                                                             CH.sub.3 H   isopropyl        fumarate                            4    CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                      H   CH.sub.3  156-158                                                                              fumarate                            5    (CH.sub.2).sub.4                                                                          H     CH.sub.3  182-183                                                                              fumarate                              5a   (CH.sub.2).sub.5                                                                          H     CH.sub.3  77-78  base                                  ______________________________________                                    

EXAMPLE 6

1-[4-(2-Methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol

18.3 g of zinc dust are gradually added to 20 g of1-[4-(2-methoxyethyl)-phenoxy]-3-nitro-3-methyl-butan-2-ol in 400 ml ofethanol and 60 ml of concentrated hydrochloric acid at 50°-60° C. Themixture is stirred at this temperature for one hour and filtered and thesolvent is evaporated off. After 200 ml of 40% strength NaOH have beenadded, the amine is extracted with methylene chloride. The hydrochlorideis obtained as described in Example 1.

Melting point: 119°-120° C.

EXAMPLE 6a

1-[2-Chloro-4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol isobtained analogously to Example 6.

Melting point: 184°-186° C. (Fumarate)

EXAMPLE 6b

1-[2-Methyl-4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol isobtained analogously to Example 6.

EXAMPLE 7

1-[4-(2-Methoxyethyl)-phenoxy]-3-methylamino-3-methyl-butan-2-ol

15 ml of acetic anhydride are added dropwise to 5.1 g of1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol in 50 ml offormic acid at room temperature. After 15 hours, 10 ml of water areadded and the mixture is evaporated to dryness. Customary working upgives 4.5 g of the N-formyl compound in the form of an oil, which isreduced with 2 g of LiAlH₄ in 50 ml of tetrahydrofuran. 3.3 g of thebase are obtained, and are converted into the hydrochloride withethanolic HCl. Melting point: 86°-88° C.

EXAMPLE 8

1-[4-(2-Methoxyethyl)-phenoxy]-3-hexylamino-3-methyl-butan-2-ol

5.1 g of 1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol arerecated with 2.2 g of caproaldehyde in 50 ml of toluene to give theazomethine, the water being distilled off. After the toluene has beenremoved, the residue is taken up in 50 ml of methanol and is reducedwith 1.9 g of NaBH₄ at 10°-15° C.

Customary working up and purification by column chromatography on silicagel gives 5 g of the base, which give 3.9 of the hydrochloride withethanolic HCl and after crystallisation with ethyl acetate/ether.

Melting point: 135°-137° C.

EXAMPLE 9

1-[4-(2-Methoxyethyl)-phenoxy]-3-isopropylamino-3-methyl-butan-2-ol

5.06 g (0.02 mol) of1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol are heated to140° C. with 4.3 g (0.02 mol) of isopropyl toluene-4-sulfphonate for twohours. After 100 ml of toluene and 100 ml of 2N NaOH have been added,the mixture is stirred for one hour and the toluene phase is separatedoff, shaken with water and evaporated in vacuo. Column chromatography onsilica gel gives 3.5 g of the abovementioned compound, which isconverted into the hydrochlorie with ethanolic HCl.

EXAMPLE 10

1-[4-(2-Methoxyethyl)-phenoxy]-3-acetamido-3-methyl-butan-2-ol

5.7 g of 1-[4-(2-Methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol arestirred with 30 ml of acetic anhydride at room temperature for 2 hoursand, after the excess anhydride has been removed, the residue is left tostand in 50 ml of 1N methanolic sodium hydroxide solution for 15 hours.Customary working up gives 5.1 g of the acetamido compound.

EXAMPLE 10

1-[4-(2-Methoxyethyl)-phenoxy]-3-nitro-3-methyl-butan-2-ol

39.5 g of 2-nitropropane and 27 g of4-(2-methoxyethyl)-phenoxy-acetaldehyde are successively added dropwiseto a solution of 2 g of sodium in 150 ml of methanol. After the mixturehas been stirred at room temperature for 15 hours, the solution ispoured onto water and acidified with 2N HCl. Extraction with CHCl₃gives, after crystallisation from diisopropyl ether, 23.3 g of the nitrocompound mentioned in the title. Melting point: 92°-94° C.

The compounds of the general formula II listed in Table 2 are preparedanalogously to Example 11 (in these Examples 12 to 15, R⁵ is hydrogen:

                  TABLE 2                                                         ______________________________________                                        (R.sup.5 = H)                                                                 Example                                                                       No.     R.sup.1 R.sup.2   R.sup.4    m.p. °C.                          ______________________________________                                        12      CH.sub.3                                                                              CH.sub.3                                                                                 ##STR10## 64-66                                    13      CH.sub.3                                                                              CH.sub.3  CH.sub.2 CH.sub.2 CH.sub.3                                                               82-84                                    14      CH.sub.3                                                                              CH.sub.2 CH.sub.3                                                                       CH.sub.3   oil                                      15      (CH.sub.2).sub.4                                                                            CH.sub.3     oil                                        ______________________________________                                    

EXAMPLE 16

4-(2-Methoxy-ethyl)-phenoxy-acetaldehyde

39 g of 4-(2-methoxy-ethyl)-phenol are heated to about 120° C., afteraddition of 0.5 g of benzyl-tributylammonium chloride, and 20.4 g of2,3-epoxypropanyl are added dropwise in the course of 15 minutes. Themixture is allowed to cool, the syrup is dissolved in CHCl₃, thesolution is washed with water and the CHCl₃ residue is purified bypreparative HPLC. 50 g of 3-[4-(2-methoxyethyl-phenoxy]-propane-1,2-diolare obtained.

Melting point: about 25° C.

A solution of 2.5 g of sodium meta-periodate in 100 ml of water and 13ml of 0.1N boric acid is added dropwise to 12 g of the above diol in 100ml of ethanol at 10°-15° C. After one hour, the NaIO₃ is filtered off,the filtrate is diluted with water and the aldehyde is extracted withCHCl₃. After the solvent has been evaporated off, 11 g of4-(2-methoxy-ethyl)-phenoxyacetaldehyde remain as the mono-ethyl acetal.

Melting point of the 2,4-dinitrophenylhydrazone: 106°-108° C.

EXAMPLE 17

Preparation of tablets

Tablets which contain the constituents given below are prepared by knownprocedures. These are suitable for the treatment of hypertension in adosage of 50 mg twice daily, for the treatment of angina pectoris in anamount of 50 mg twice daily, and for the treatment of arrhythmias in anamount of 100 mg three times daily.

    ______________________________________                                                           Tablet A                                                                             Tablet B                                            ______________________________________                                        1-[4-(2-Methoxyethyl)-phenoxy]-                                               3-amino-3-methyl-butan-2-ol                                                                        50     mg    100   mg                                    Lactose              189    mg    134   mg                                    Maize starch         25     mg    25    mg                                    Magnesium stearate   1      mg    1     mg                                    ______________________________________                                    

EXAMPLE 18

Preparation of eye drops

Eye drops which contain the following constituents can be prepared in aknown manner. They can be used in a dose of one to two drops per eyeonce or twice daily, preferably one drop twice daily:

1-[4-(2-Methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol 0.5 g

Isotonic aqueous solution (Ringer's solution) to 100 ml.

I claim:
 1. Substituted phenoxyalkanolamines andphenoxyalkanol-cycloalkylamines of the general formula I ##STR11## inwhich R¹ and R², which can be identical or different, denote alkylgroups with in each case 1 to 4 carbon atoms, or R¹ and R² togetherdenote the group --(CH₂)_(n) --, wherein n is the number 4 or 5, R³denotes hydrogen, R⁴ denotes an alkyl group with 1 to 4 carbon atoms orthe cyclopropylmethyl group and R⁵ denotes hydrogen, halogen or alkyl,and acid addition salts thereof.
 2. Phenoxyalkanolamines andphenoxyalkanol-cycloalkylamines according to claim 1, of the generalformula I, in which R₁ and R₂ each denote alkyl.
 3. Phenoxyalkanolaminesand phenoxyalkanol-cycloalkylamines according to claim 1 of the generalformula I, in which R¹ and R² each denote methyl and R⁴ is methyl orcyclopropylmethyl.
 4. Phenoxyalkanolamines andphenoxyalkanol-cycloalkylamines according to claim 1 of the generalformula I, in which R⁵ denote hydrogen.
 5. A compound of claim 1 whichis 1-[4-(2-methoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol.
 6. Acompound of claim 1 which is1-[4-(2-cyclopropylmethoxyethyl)-phenoxy]-3-amino-3-methyl-butan-2-ol.7. Substituted phenoxynitroalkanols andphenoxyhydroxyalkyl-nitrocycloalkanes of claim 1 of the general formulaII ##STR12## in which R¹ and R², which can be identical or different,denote alkyl groups with in each case 1 to 4 carbon atoms, or R¹ and R²together denote the group --(CH₂)_(n) --, wherein n is the number 4 to5, R⁴ denotes an alkyl group with 1 to 4 carbon atoms or thecyclopropylmethyl group and R⁵ denotes hydrogen, halogen or alkyl. 8.Substituted phenoxyacetaldehydes of claim 1 of the general formula III##STR13## in which R⁴ denotes an alkyl group with 1 to 4 carbon atoms orthe cyclopropylmethyl group and R⁵ denotes hydrogen, halogen or alkyl.